What could cause isolated gamma-glutamyl transferase (GGT) elevation with normal liver enzymes and bilirubin in an elderly patient on valproic acid (valproate)?

Isolated GGT Elevation in an Elderly Patient on Valproic Acid

Valproic acid is the most likely cause of isolated GGT elevation in an elderly patient with normal liver enzymes and bilirubin, and typically does not require discontinuation unless other liver parameters become abnormal. 1

Significance of Isolated GGT Elevation

• GGT (gamma-glutamyl transferase) elevation alone is generally considered a poor indicator of significant liver injury and insufficient to qualify as drug-induced liver injury (DILI) 1
• Isolated GGT elevations can occur in the absence of underlying liver disease and are not typically used as exclusion criteria in clinical trials 1
• GGT levels in patients may range widely (from low normal to >400 U/L) without indicating serious hepatic dysfunction 1

Valproic Acid as the Primary Cause

• Valproic acid is known to cause alterations in liver function tests, including isolated GGT elevation 2, 3
• The drug can affect hepatic function through multiple mechanisms:
  • Formation of reactive metabolites 3, 4
  • Inhibition of fatty acid β-oxidation 3, 4
  • Induction of oxidative stress 3
  • Mitochondrial dysfunction 4

Other Potential Causes to Consider

• Alcohol consumption (even moderate amounts can elevate GGT) 1
• Enzyme induction from other medications 1
• Early stages of non-alcoholic fatty liver disease (NAFLD), which can be exacerbated by valproic acid 3, 4
• Age-related changes in liver metabolism 1

Monitoring and Management Approach

1. Continue monitoring liver function:

   • Regular assessment of complete liver panel (ALT, AST, ALP, bilirubin) 2, 3
   • Pay particular attention if GGT rises above 2× ULN, as this may predict persistent liver enzyme abnormalities 5

2. Assess for development of other liver abnormalities:

   • Watch for elevation of ALT/AST or alkaline phosphatase 1
   • Monitor for symptoms of hepatotoxicity (fatigue, jaundice, right upper quadrant pain) 6

3. Consider dose adjustment:

   • If GGT continues to rise significantly or other liver enzymes become abnormal, dose reduction (approximately 10 mg/kg/day) may normalize liver function tests 2
   • Dose adjustment rather than discontinuation is often sufficient 2

4. Risk stratification:

   • Elderly patients generally have lower risk of severe VPA hepatotoxicity compared to children under 2 years 6
   • Polytherapy with other antiepileptics increases risk 6
   • Assess for metabolic disorders that may increase risk 6, 4

Important Caveats

• Isolated GGT elevation should not be dismissed entirely, as some research suggests it may indicate early DILI even when conventional diagnostic criteria are not met 5
• If GGT elevation is accompanied by symptoms or other liver enzyme abnormalities, more thorough evaluation is warranted 5, 3
• Consider carnitine supplementation as a potential protective strategy if continuing valproic acid with persistent GGT elevation 3
• Therapeutic drug monitoring of valproic acid levels may be beneficial in optimizing dosage 3